Targeting SARS-COV-2 3-Chymotrypsin-Like Cysteine Protease and NSP7-NSP8-RDRP Core Replicase Complex for Inhibitory Drug Design Against COVID-19: Molecular Docking of TCMSP Compounds and Novel Redesigned Ligands

Abstract

The COVID-19 pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) precipitated a global health crisis. Despite significant progress in attempts to eliminate the pathogen, new variants and subvariants responsible for the resurgence of cases continue to emerge. There is thus an urgent need to identify promising drug leads for devising new and effective therapeutic strategies against COVID-19. Among the identified prospective targets against SARS-CoV-2 to date, 3-chymotrypsin-like cysteine protease (3CLpro) and NSP7-NSP8-RdRP core replicase complex are particularly promising owing to their key roles in viral polyprotein processing and genome replication and transcription, respectively. These proteins were thus targeted for molecular docking with 6,699 curated compounds from the Traditional Chinese Medicines Systems Pharmacology (TCMSP) database. The top 20 binders for each enzyme were selected based on their binding energies (∆G) and were further evaluated for compliance with Lipinski’s Rule of Five (Ro5). Ligand redesigning via fragment linking, merging, and growing techniques of the fragment-based drug discovery approach was then performed using the top 20 binders for further optimizing of binding affinities to the selected target proteins. Among the 6,699 docked TCMSP ligands, MOL011100 (∆G = -10.590 kcal/mol), MOL011124 (∆G = -10.110 kcal/mol), and MOL008643 (∆G = -9.304 kcal/mol) exhibited the highest binding affinities to the active site of 3CLpro. MOL010178 (∆G = -8.868 kcal/mol), MOL011000 (∆G = -8.303 kcal/mol), and MOL010193 (∆G = -8.293 kcal/mol) exhibited the highest binding affinities to the allosteric binding sites of NSP7 and NSP8 or RdRP. Among these top-binding TCMSP compounds, four were also found to have potential for dual-target inhibition as they exhibited strong binding affinities to both enzymes. These were MOL011100 (3CLpro, ∆G = -10.590 kcal/mol; RdRP, ∆G = -8.303 kcal/mol), MOL008643 (3CLpro, ∆G = -9.304 kcal/mol; RdRP, ∆G = -7.849 kcal/mol), MOL009562 (3CLpro, ∆G = -8.803 kcal/,mol; RdRP, ∆G = -8.072 kcal/mol), and MOL008641 (3CLpro, ∆G = -8.757 kcal/mol; RdRP, ∆G = -7.818 kcal/mol). All top-binding ligands to 3CLpro, except MOL0011097, and those to RdRP satisfied Lipinski’s Ro5. Moreover, among the 160 novel redesigned ligands for 3CLpro, the top binders were R001A TAYAG_159 (∆G = -10.670 kcal/mol) R002A TAYAG_61(∆G = -10.460 kcal/mol), R003A TAYAG_79 (∆G = -10.350 kcal/mol), while among the 120 novel redesigned ligands for RdRP, the top binders were R001B NGO_006 (∆G = -10.470 kcal/mol), R002B NGO_050 (∆G = 10.280 kcal/mol, and R003B NGO_003 (∆G = 10.010 kcal/mol). All the top redesigns satisfied Lipinski’s Ro5, indicating their suitability for utilization in further studies involving drug development and lead optimizing against SARS-CoV-2.